Highly active antiretroviral therapy (HAART) has altered the course of Human Immunodeficiency Virus (HIV) infection. Treatment with a combination of nucleoside analogs and protease inhibitors results in profound inhibition of HIV replication, as well as quantitative and qualitative improvements in host immune function. T-cell counts increase to varying degrees in patients on HAART therapy. The increase in CD4+ T cells may result from homeostatic expansion of existing T-cells, as well as production of new T-cells from the thymus. Several groups have reported that HIV-infected individuals receiving HAART produce thymic-derived naïve T-cells, as determined by T-cell receptor (TCR) excision circles (TREC).1-4 However, it remains unclear whether HAART increases thymic T-cell output by reducing the pathogenic effects of HIV on the thymus, or by a direct drug effect on the thymus.
A recent report demonstrated an increase in TREC-positive cells from the peripheral blood of HIV-negative health-care workers who received nelfinavir, Zidovudine, and Lamivudine HAART for 28 days for post-HIV-exposure prophylaxis (PEP),5 raising the possibility that HAART may directly impact thymic output.
Increasing evidence suggests that HIV protease inhibitors may have intrinsic immunomodulatory activity. These effects include inhibition of proteasome function,6 anti-tumor effects in models of Kaposi's sarcoma,7 reduced cellular activation associated with inhibited NF-κB activation,8 direct inhibition of calpain,9 matrix metalloprotinease,7 and aspartyl proteases produce by PCP,10 and Candida,11 as well as anti-apoptotic effects.12 These effects also occur in vivo, since mice implanted with Kaposi's sarcoma and treated with Ritonavir experience significant tumor regression and NOD/SCID mice implanted with adult T-cell leukemia cells experience reduced tumor growth in the presence of Ritonavir.8, 13 In addition, treatment of mice with nelfinavir/Ritonavir reduces mortality due to poly-microbial sepsis, 14 Fas-induced hepatitis,15 SEB/D-gal induced shock15 and reduces neuronal injury due to cerebral ischemia.15 
Needed in the art of disease treatment is a method of increasing the number of naïve T-cell numbers in an HIV-negative patient using protease inhibitors.